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Blocking the complement system was shown to improve the outcome of experimental pneumococcal meningitis. Complement factor H (FH) is a complement regulatory protein inhibiting alternative pathway activation but is also exploited by the pneumococcus to prevent complement activation on its surface conferring serum resistance.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>In a nationwide prospective cohort study of 1009 episodes with community-acquired bacterial meningitis, we analyzed whether genetic variations in <jats:italic>CFH<\/jats:italic> influenced FH cerebrospinal fluid levels and\/or disease severity. Subsequently, we analyzed the role of FH in our pneumococcal meningitis mouse model using FH knock-out (<jats:italic>Cfh<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>) mice and wild-type (wt) mice. Finally, we tested whether adjuvant treatment with human FH (hFH) improved outcome in a randomized investigator blinded trial in a pneumococcal meningitis mouse model.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>We found the major allele (G) of single nucleotide polymorphism in <jats:italic>CFH<\/jats:italic> (rs6677604) to be associated with low FH cerebrospinal fluid concentration and increased mortality. In patients and mice with bacterial meningitis, FH concentrations were elevated during disease and <jats:italic>Cfh<\/jats:italic><jats:sup>\u2212<jats:italic>\/<\/jats:italic>\u2212<\/jats:sup> mice with pneumococcal meningitis had increased mortality compared to wild-type mice due to C3 depletion. Adjuvant treatment of wild-type mice with purified human FH led to complement inhibition but also increased bacterial outgrowth which resulted in similar disease outcomes.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>Low FH levels contribute to mortality in pneumococcal meningitis but adjuvant treatment with FH at a clinically relevant time point is not beneficial.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s12974-019-1675-1","type":"journal-article","created":{"date-parts":[[2019,12,28]],"date-time":"2019-12-28T10:02:28Z","timestamp":1577527348000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Complement factor H contributes to mortality in humans and mice with bacterial meningitis"],"prefix":"10.1186","volume":"16","author":[{"given":"E. 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The MeninGene study was approved by the medical ethical committee of the Academic Medical Centre, Amsterdam, the Netherlands. Animal experiments were approved by the Institutional Animal Care and Use Committee of the Academic Medical Center Amsterdam.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"RBP, DW, and TWK are co-inventors of a patent describing potentiating anti-FH antibodies and uses thereof. All other authors declare that they have no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"279"}}